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Adding atezolizumab to platinum-based chemotherapy significantly improved progression-free survival in patients with previously untreated locally advanced or metastatic urothelial carcinoma, according to results from the phase III IMvigor130 study.
Sandra Horning, MD
Adding atezolizumab (Tecentriq) to platinum-based chemotherapy significantly improved progression-free survival (PFS) in patients with previously untreated locally advanced or metastatic urothelial carcinoma (mUC), according to results from the phase III IMvigor130 study reported by Genentech, the manufacturer of the PD-L1 inhibitor.1
The company also reported that a positive trend in the coprimary endpoint of overall survival (OS) was noted at the interim analysis, but the data are not yet mature. No new safety signals emerged with the atezolizumab combination as compared with historical data. Genentech plans to share the IMvigor130 data at an upcoming medical conference.
“IMvigor130 is the first positive phase III study of a cancer immunotherapy combination in previously untreated advanced bladder cancer, an aggressive disease with high unmet need,” Sandra Horning, MD, chief medical officer and head of Global Product Development, Genentech, said in a press release.
“These results support our broad clinical development program for Tecentriq in bladder cancer, as well as our approach of combining immunotherapy with chemotherapy or other medicines to improve patient outcomes, and we look forward to discussing them with health authorities,” added Horning.
The multicenter, partially blinded phase III IMvigor130 study included 1213 patients with locally advanced or mUC who had not received prior treatment for advanced or metastatic disease. Patients were randomized to receive atezolizumab alone; atezolizumab combined with platinum-based chemotherapy comprising gemcitabine with either cisplatin or carboplatin; or the same chemotherapy option combined with placebo.
Atezolizumab is currently approved by the FDA for the frontline treatment of patients with locally advanced or mUC in PD-L1—positive patients who ineligible for cisplatin-containing chemotherapy or those who are not eligible for any platinum-based chemotherapy, regardless of PD-L1 status.
The approval was based on data from the single-arm phase II IMvigor210 trial. In a study cohort of 119 cisplatin-ineligible, treatment-naive patients, the objective response rate (ORR) with atezolizumab was 23.5% (n = 28; 95% CI, 16.2-32.2), including a complete response (CR) rate of 6.7%.2
The treatment-naive IMvigor210 cohort enrolled 123 patients with cisplatin-ineligible locally advanced or mUC at 47 locations in North America and Europe between June 9, 2014, and March 30, 2015. Patients received 1200 mg of atezolizumab IV every 3 weeks until progression. The primary endpoint was ORR, with secondary outcomes measures including PFS and OS.
Among the 123 patients, 119 received at least 1 dose of atezolizumab. There was an association between tumor mutation load and response. The median PFS and OS were 2.7 months (95% CI, 2.1-4.2) and 15.9 months (95% CI, 10.4 to not estimable), respectively.
The median duration of response was not yet reached. Among patients with PD-L1 expression ≥5% (n = 32), the ORR was 28.1% (95% CI, 13.8-46.8), including a CR rate of 6.3%. In patients with PD-L1 expression <5%, the corresponding rates were 21.8% (95% CI, 13.7-32.0) and 6.9%, respectively.
The IMvigor 210 cohort on which this approval was based included an all-comer population of 316 patients with inoperable locally advanced or mUC who progressed after receiving platinum-based chemotherapy.3 Data from 310 patients were evaluable. The patients had been heavily pretreated, with 40% of patients undergoing 2 or more prior systemic regimens in the metastatic setting and 74% of patients receiving previous cisplatin-based chemotherapy.
Atezolizumab was administered at 1200 mg intravenously on the first day of each 21-day cycle until no further clinical benefit was demonstrated. Median treatment duration was 12 weeks (range, 0-46 weeks). The coprimary study endpoints were ORR, as assessed by central review and the investigators, both by modified RECIST v1.1. Secondary endpoints included duration of response, PFS, OS, and safety.
At a median follow-up of 14.4 months, ORR was 14.8% (95% CI, 11.1-19.3; n = 46/310) in all comers, 26% (95% CI, 17.7-35.7; n = 26/100) in patients with PD-L1 expression ≥5%, and 9.5% (95% CI, 5.9-14.3; n = 20/210) in those with PD-L1 expression <5%. In a subgroup of 59 patients from the IMvigor 210 study who progressed after neoadjuvant or adjuvant platinum-based chemotherapy, the ORR was 22% (95% CI, 12.3-34.7).
Complete response rates in the overall, higher—PD-L1, and lower–PD-L1 groups were 5.5%, 12%, and 2.4%, respectively. Partial response rates were 9.4%, 14%, and 7.1%, respectively. The median duration of response was 12.7 months (range, 2.1+ to 12.7) in the higher PD-L1 population, and had not yet been reached in either the overall group or the lower PD-L1 cohort.
Of note, the second-line indication was an accelerated approval, contingent on the results of a confirmatory trial. In May 2017, Genentech reported that in the confirmatory phase III IMvigor211 trial, atezolizumab missed the primary endpoint of improving OS versus chemotherapy in the second-line setting for patients with locally advanced or mUC.
Genentech has 4 ongoing trials examining atezolizumab as a single agent and in combination regimens in early and advanced bladder cancer.
Based on a separate cohort from the IMvigor210 trial, atezolizumab also received an approval as a treatment for patients with locally advanced or mUC whose disease progressed during or after platinum-based chemotherapy, or within 12 months of receiving platinum-containing chemotherapy, either before or after surgery.